title: Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling.
abstract: Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean >10-fold) in >60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction of mitochondrial ROS was rarely observed. Elevated ROS was found to be associated with lowered glutathione levels and depletion of antioxidant defense proteins. We also show for the first time that the levels of ROS generated were able to strongly promote the proliferation of AML cell lines, primary AML blasts, and, to a lesser extent, normal CD34(+) cells, and that the response to ROS is limited by the activation of the oxidative stress pathway mediated though p38(MAPK). Consistent with this, we observed that p38(MAPK) responses were attenuated in patients expressing high levels of ROS. These data show that overproduction of NOX-derived ROS can promote the proliferation of AML blasts and that they also develop mechanisms to suppress the stress signaling that would normally limit this response. Together these adaptations would be predicted to confer a competitive advantage to the leukemic clone.
authors.affiliation: Department of Haematology, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Hole
authors.forename: Joanna
authors.initials: J
authors.lastname: Zabkiewicz
authors.forename: Chinmay
authors.initials: C
authors.lastname: Munje
authors.forename: Zarabeth
authors.initials: Z
authors.lastname: Newton
authors.forename: Lorna
authors.initials: L
authors.lastname: Pearn
authors.forename: Paul
authors.initials: P
authors.lastname: White
authors.forename: Nuria
authors.initials: N
authors.lastname: Marquez
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hills
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.forename: Alex
authors.initials: A
authors.lastname: Tonks
authors.forename: Richard L
authors.initials: RL
authors.lastname: Darley
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D016022:Case-Control Studies; D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione